Among the candidate genetic loci for difference in alcohol's toxic effects are genes encoding alcohol metabolic enzymes and thiamine-dependent enzymes including transketolase. Transketolase has previously been hypothesized to be genetically variant in individuals vulnerable to Wernicke-Korsakoff Disease. Collaboratively with Drs. Martin and Singleton, who cloned a transkelotase cDNA, we have completed a direct analysis of the transkelotase gene using the SSCP method in 20 Korsakoff patients compared to controls. None of five polymorphisms we found showed an association to Korsakoff's disease in this small sample, however, six rare SSCP variants are being sequenced. Class III ADH (ADH5) is an unusual ADH with a role in the metabolism of formaldehyde (Koivasalo, 1990). This enzyme could thus play a role in methanol toxicity and in the metabolism of methanol found as a trace contaminant in alcoholic beverages. We have shown that ADH is present in significant amounts in the brain. We previously cloned the human class III alcohol dehydrogenase, characterized its sequence and expression and discovered a moderately informative human Sac I RFLP. We have located the ADH5 gene to the same chromosomal region in mouse and man, approximately 5 cm from the other ADH genes. We have also located several ADH pseudogenes.